Project summary Non-medical use of prescription substances (NMUPS) is the use of a medication without a prescription, in ways other than prescribed, or for the experience or feelings elicited. The picture of NMUPS among young adults is bleak. Each year an estimated 2.4 million North Americans, or ~6,600 initiates per day, use prescription drugs non-medically for the first time, more than one-half are females. NMUPS is highest among young adults aged 18 to 25, with 5.3% reporting current NMUPS. NMUPS is associated with college drop out, worse employment outcomes, sexual victimization, health-jeopardizing behaviors such as driving under the influence, and high-risk sexual behavior, and psychiatric symptoms including suicide. Among adolescents, U.S. college students and young adults, it is also associated with poly-substance use including cocaine, ecstasy, and amphetamine-like substances. More than half of all drug-related emergency room visits in the U.S. can now be linked to NMUPS. NMUPS is a clear threat to public health. Deaths attributable to unintentional drug overdose of opioids and analgesic exceed those for cocaine and heroin, and continue to increase. Moreover, the death toll across all age groups from NMUPS exceeds those for all other illicit substances. Factors driving NMUPS include, but are not limited to, misperceptions about safety, increasing drug availability, along with individual risk factors and motivations. Despite the high prevalence of NMUPS, concomitant death rates, and comorbidity, the basic genetic epidemiology of NMUPS in terms of genetic and environmental risks remains unknown. Without a thorough, empirical understanding of these risk factors, prevention and intervention programs will continue to remain limited. Knowledge of these risks factors and their relation to other substances will also determine whether funding the development of NMUPS-specific diagnostic assessments is also merited. We propose secondary data analyses using two large population-based samples varying by sex, age and ethnicity to address three aims. The first is to describe the patterns of NMUP analgesics and stimulants in two population-based samples of young adults and college-aged students. We will then use basic genetic epidemiological methods to estimate the contribution of genetic and environmental risks in NMUP analgesics and stimulants. Next, advanced genetic epidemiological will be used to estimate the degree of genetic and environmental overlap between NMUP analgesics and stimulants and other licit and illicit substance use. Finally, we determine whether polygenic risk for alcohol, nicotine, cannabis, cocaine, and heroin use and substance use predicts NMUP analgesics and stimulants while examining sex, age and ethnic differences. This knowledge will significantly improve our understanding of the genetic and environmental risks behind the emerging, dangerous trends in NMUPS.